Process for heterogeneous nucleophilic substitution reactions

ABSTRACT

The invention relates to a process for nucleophilic substitution reactions. According to the invention the reaction is carried out in a heterogeneous system, consisting of a solid and a dissolved reactant, one or several organic solvents, one or several linear polyether derivatives, and/or amino compounds and water. 
     The volume of the water is preferably at the most 100% of the volume of the organic solvent and more preferably 5%. 
     According to the invention the anhydrous reaction medium which is difficult to ensure, is not necessary and the use of the expensive and in industrial scales unavailable crown ethers is eliminated.

The present invention is related to a process for nucleophilicreactions.

According to the invention the reaction is carried out in aheterogeneous system containing one reactant in the solid state, theother in a dissolved state and the reaction mixture contains one orseveral organic solvents, one or several linear polyether derivativesand/or amino compounds and water.

In the course of the process of the invention, preferablywater-inmiscible solvents, such as aromatic, and aliphatic hydrocarbons,particularly benzene and homologues thereof may be used as organicsolvents. Other solvents, which are stable under the reaction conditionsand dissolve one component of the system, may also be employed.

As linear polyether derivatives preferably such polyether derivativesare used, which consist of lower alkylene and oxygen units, such aspolymerizates of lower glycols, such as polyethylene glycol.

As amino compounds preferably tri(lower)alkyl amines, such astriethylamine, may be employed.

The reaction may be carried out in the presence of linear polyetherderivatives only, amino compounds only or in the presence of both. Thereaction may also be performed in the presence of amino compounds, whichmay be prepared by replacing the terminal hydroxy group of linearpolyether derivatives by a secondary amino group. The latter compoundsmay contain a di(lower alkyl)amino or a cyclic amino group, such as a1-piperidyl group as a terminal amino group.

The amount of water that may be in the reaction mixture is varied withina wide range. The water content is preferably about 0.5 to 50%calculated relative to organic solvents therein.

Lower alkyl stands for an alkyl group containing 1 to 4 carbon atoms.

In the nucleophilic substitution reactions carried out with anions, theanion is preferably used in the form of a salt thereof. The alkali saltsdo not dissolve or dissolve poorly, in organic solvents.

Such reactions are typically carried out in a hetergeneous system. Thealkali salt or hydroxide is used in an aqueous medium and the otherreactant is used in an organic solvent solution.

The substance transport between the layers is a critical factor of theprocess. The transport was originally promoted by increasing thedispersity, by using emulsifying agents.

In 1951 (C. R. Acad. Sci., Ser. C. 232, 1424 (1951) the phase transfercatalytic effect of quaternary ammonium salts was recognized. In 1965generally suitable methods were elaborated (Dutch Patent ApplicatiionNo. 6,412,937) and the phenomenon has been explained from a theoreticalpoint of view as well (J. A. C. S. 93, 195 (1971). With the aid of theabove results the salt in aqueous solution could be readily reacted withthe substrate.

For industrial purposes however, processes, wherein the salt need not bepreviously dissolved, are more preferable.

It has been reported that the outstanding complex forming capability ofcrown ethers with alkali ions may be used for activation of the anionaccompanying these ions (J. A. C. S. 89, 7017 (1967).

This phenomenon is used for conducting the reactions of the alkali saltsby dissolving the substrate and the crown ether in an organic solventand by moving the salt in the reaction mixture by a stirrer as adispersion. For a similar purpose cryptates, phosphoric acid amides andsome polyamino compounds may be used as well (Synth. 1975, 805).

The price of the above compounds is very high, and the use thereofrequires an anhydrous medium.

We have surprisingly found, that these compounds containing polyetherchains of different length show an outstanding catalytic activity ifapart from the solid and organic layers there is a small amount of waterpresent as well. This occurred in the case of some amines too.

This type of cocatalysis is a new method for realization ofphase-transfer reactions and thus a similar or a better effect could beachieved than that obtained with crown ethers, when using the otherwiseweak polyethylene glycol catalyst. Thus polyethylene glycol may be usedin preparative laboratory or industrial practice, as the reaction andthe processing of the reaction mixture is very simple, and the costs ofthe catalyst are much lower than the costs of the catalysts used so far.

A further advantage of the process according to the invention is thefact that an excess of alkali-, alkali earth metal- or ammonium salts orhydroxides is not necessary or a smaller amount of excess is necessarythan in the case of the known processes.

As the process of the invention is suitable for different nucleophilicreactions, by chosing the best reactants the process of the inventionmay be used in the field of the preparative organic chemical practiceand in the big field of industry. The following examples are mentionedas suitable nucleophilic reactants without limiting the invention tothese reactants: alkali or alkali earth metal hydroxides, halides,sulfides, hydrogen sulfides, phenolates, enolates, cyanides, rhodanides,cyanates, nitrates, azides, cyanamides, carboxylates, sulfonates, butorganic compounds containing loosened carbon-hydrogen bond andmercaptane salts may also be used. As a substrate - another reactant ofthe reaction - all compounds suitable for nucleophilic reactions - maybe employed. Such compounds without limiting the scope of the inventionto these compounds, are compounds containing carbon-halogen bond, suchas unsubstituted and substituted benzyl halides.

The further details of the invention are illustrated by the followingexamples without limiting the scope of the invention to the examples.

EXAMPLE 1

To a 25 ml. flask equipped with a stirrer and reflux 10 ml. of benzene,0.15 g. of polyethylene glycol of average molecular weight of 300, 3.25g. (0.05 mole) of potassium cyanide and 0.5 ml. of water are added. Thereaction mixture is gently boiled under stirring and under reflux for 15minutes whereafter 5.7 ml. (0.05 mole) of benzyl chloride are added andthe reaction mixture is further boiled under stirring and reflux.

The reaction is followed by gas chromatography. The conversion iscompleted in 4.5 hours.

The reaction mixture is then cooled, filtered and the precipitate iswashed with benzene. The combined benzene filtrates are dried withmagnesium sulphate and the benzene is removed by distillation and theresidue is distilled.

The main cut is collected at 15 torr at a temperature of 105° to 120° C.Yield: 4.69 g. (80.2%) of benzyl cyanide.

EXAMPLE 2

To a 100 ml. flask equipped with a stirrer and reflux 50 ml. of toluene,0.75 g. of polyethylene glycol of average molecular weight of 300, 0.5ml. of water, 0.5 ml. of triethylamine and 24.5 g. (0.25 mole) ofpotassium acetate are introduced. The reaction mixture is maintained at100° C. under stirring for 15 minutes and 28.5 ml. (0.25 mole) of benzylchloride are added whereafter the mixture is further heated for 3.5hours at 100° C. under steady stirring.

The reaction mixture is cooled, filtered and the precipitate is washedwith toluene and the combined toluene filtrates are dried with sodiumsulphate, the toluene is distilled off and the residue is distilled atatmospheric pressure. The main cut is collected at 210°-225° C.

Yield 29.96 g. (80.5%) of benzyl acetate.

EXAMPLE 3

The process of Example 1 is used but instead of polyethylene glycol ofaverage molecular weight of 300 a polyether in the same amount is usedwhich was prepared from polyethylene glycol of an average molecularweight of 300 by conversion of the terminal group into a 1-piperidylgroup. According to gas chromatographic analysis the conversion iscompleted within 4 hours.

Yield: 4.96 g. (85%) of benzyl cyanide.

EXAMPLE 4

The process of Example 1 is used but instead of the polyethylene glycolof molecular weight 300,0.10 g. of triethylamine is used as a catalyst.According to gas chromatographic analysis the conversion is completedwithin 4.5 hours.

Yield: 4.66 g. (80%) of benzyl cyanide.

EXAMPLE 5

To a 250 ml. flask equipped with a stirrer and reflux 40 ml. of benzene,0.5 g. of polyether of a molecular weight of 300 containing 1-piperidylterminal group, 2 ml. of water and 9.8 g. (0.15 mole) of potassiumcyanide are introduced. The reaction mixture is gently boiled whereafter28.4 g. (0.15 mole) of 3,4-dimethoxy-benzyl-chloride are added.

The reaction mixture is stirred for 3.5 hours under mild heating. Theconversion is substantially completed.

The mixture is cooled, filtered and the precipitate is washed withbenzene. The combined benzene filtrates are dried with magnesiumsulphate and benzene is distilled off and the residue is distilled. Themain cut is collected at 15 torr and at 190°-200° C.

Yield: 20.0 g. (75%) of 3,4-dimethoxy-benzyl cyanide.

EXAMPLE 6

The process of Example 5 is used but instead of polyethylene glycolhaving a 1-piperidyl terminal group of an average molecular weight of300, polyethylene glycol of an average molecular weight of 300 is used,in the same amount.

The conversion is substantially completed within 3.5 hours. Yield: 19.8g. (74%) of 3,4-dimethoxy-benzyl cyanide.

EXAMPLE 7

The process of Example 5 is used but as a starting material instead ofthe purified 3,4-dimethoxy-benzyl chloride, 39.1 g. of the residue isused which is obtained by evaporation of the reaction mixture servingfor the preparation of 3,4-dimethoxy-benzyl chloride, containing 28.4 g.of 3,4-dimethoxy-benzyl chloride.

Yield: 20.2 g. (76%) of 3,4-dimethoxy-benzyl cyanide.

EXAMPLE 8

To a 250 ml. flask equipped with a stirrer and reflux 20 ml. of benzene,0.5 g. polyether having a 1-piperidyl terminal group of an averagemolecular weight of 300, 0.5 ml. of triethylamine, 7.35 g. (0.15 moles)of sodium cyanide and 10 ml. of water are introduced. The reactionmixture is gently heated under reflux for 15 minutes, whereafter 145 g.of 19.6% 3,4-dimethoxy-benzyl chloride in benzene are added.(3,4-dimethoxy-benzyl chloride content: 0.15 moles).

The reaction mixture is heated for 3.5 hours under stirring and reflux.The conversion is completed.

The mixture is cooled, the aqueous layer is separated; and the organiclayer is washed twice with 20 ml. of water. The benzene solution isdried with magnesium sulphate, evaporated and the residue isfractionated in vacuo.

The main cut is collected at 190°-200° C. Yield: 19.5 g. (73.4%) of3,4-dimethoxy-benzyl cyanide.

What we claim is:
 1. A process for carrying out a nucleophilicsubstitution reaction which comprises the step of conducting thereaction in a heterogeneous system containing a nucleophilic reagentselected from the group consisting of alkali metal, alkali earth metalor ammonium cyanides and carboxylates and a benzyl halide substratewherein one of said nucleophilic reagent and said benzyl halidesubstrate is in a solid state and the other is in a dissolved state, awater-immiscible solvent, water, and a phase transfer agent selectedfrom the group consisting of a polymerizate of a lower alkylene glycol,a polymerizate of a lower alkylene glycol with a dilower alkylaminegroup or 1-piperidyl group terminally substituted thereon, a mixture ofa polymerizate of a lower alkylene glycol and a triloweralkyl amine, andmixtures thereof.
 2. The process defined in claim 1 which comprisesconducting the reaction wherein the volume of water is at most 100% ofthe volume of the water immiscible solvent.
 3. The process defined inclaim 2 wherein the volume of water is 5% of the volume of the waterimmiscible solvent.
 4. The process defined in claim 1 wherein the phasetransfer agent is a polyethylene glycol.
 5. The process defined in claim1 wherein the water immiscible solvent is benzene or toluene.
 6. Theprocess defined in claim 1 wherein the phase transfer agent is apolyethylene glycol having a piperidyl terminal group.
 7. The processdefined in claim 1 wherein the phase transfer agent is a mixture of alinear lower alkylene glycol and a trilower alkyl amine.
 8. The processdefined in claim 7 wherein the phase transfer agent is a mixture of apulyethylene glycol having a piperidyl terminal group and triethylamine.9. The process defined in claim 1 wherein the nucleophilic reactant isan alkali cyanide.
 10. The process defined in claim 1 wherein thenucleophilic reactant is an alkali acetate.
 11. The process defined inclaim 1 wherein the benzyl halide is substituted by a methoxy group.